The present invention relates generally to adhesives, more specifically it relates to medical adhesives, and particularly it relates to tissue adhesives which exhibit high bio-compatibility, excellent tensile properties, are bio-absorbable, do not interfere with the healing processes and are easily applied to various tissues. The present invention is also particularly well suited for controlling complex, vigorous bleeding emanating from large surface areas, specifically the visceral organs, lungs and the vascular system.
The use of adhesive compounds in wound sealing and hemorrhage control dates back to the sixteenth century. Early sealants consisted of rosewater, turpentine and eggs and were used in conjunction with ligatures. Biologic and Synthetic Polymer Networks, Ed. O. Kramer, Elsevier Applied Science, New York (1988). While such techniques offered marked improvement over cautery, little effort was made to advance the art until the Spanish Civil war when plasterized cotton was introduced. Leo Mandelkern, An Introduction to Macromolecules 2nd ed.; Springer Verlag, New York (1983). Early cotton-based adhesives were little more than surgical packings and could not control large, profusely bleeding visceral surfaces.
Subsequent wars brought new experiments with adhesives to aid in controlling the massive, vigorously bleeding hemorrhages associated with battlefield injuries. In the 1940s, trauma surgeons began experimenting with fibrin sealants, however, these did not possess the strength required to adequately control vigorous bleeding wounds and W.W. II field hospitals returned to plasterized cotton. Turner Alfrey et al., Organic Polymers, Prentice Hall, New Jersey (1967). Technological advances in polymer chemistry led to the development of cyanoacrylates that were first used as tissue adhesives in the Vietnam war. Since that time, moderate advances have been made in the development of modern tissue adhesives, but none have adequately addressed the technical and biological complexities associated with vigorous bleeding homeostasis.
Severe traumatic injuries result in massive intra-abdominal hemorrhages in approximately 10 to 25% of cases. Uncontrolled bleeding and transfusion-associated complications make up the majority of deaths in these patients. The current recommended standard of care for treating intra-abdominal bleeding is a process called packing which utilizes pressure and nylon gauze to contain the blood flow. A. Sauaia, et al., Epidemiology of Trauma Deaths: a Reassessment, Journal of Trauma (February 1995). However, in spite of advances in nearly every other branch of medicine, mortality rates associated with severe abdominal trauma remain high. Traditional methods of tissue closure including tapes, sutures and staples are completely inadequate when the effected area is the surface of a visceral organ that has been severely lacerated or ruptured.
Tapes, sutures and staples fail to assure fluid-tight closures and often require surgical removal even when used as clinically indicated. These disadvantages are further exacerbated by the scarring, additional tissue damage and inflammation often associated with such techniques. The exposed tissue at the suture site can become infected requiring frequent cleaning and treatment with topical as well as systemic antibiotics. Another significant drawback to sutures, staples and tapes is their inability to be used in combination with microsurgical techniques. Consequently, the development of a versatile bio-compatible, non-toxic tissue adhesive, suitable for controlling vigorous bleeding over large surface areas, that has high adhesive strength and excellent tensile properties would constitute a major medical and technical advance.
Multiple factors must be considered when evaluating candidate tissue adhesives. The most important of these include bio-compatibility, resistance to fracture, pliability, adhesive strength, ease of application, and rapid curing time. Materials which possess ideal bio-compatibility are immunologically inert, do not interfere with wound healing, do not induce strictures or scars, are bio-absorbable and completely non-toxic. Due to these demanding criteria, it has been extremely difficult to find an ideal material.
Various forms of wound sealant technologies exist including fibrin sealants, gelatin resorcin aldehyde adhesives, albumin based tissue adhesives, acrylates, tissue welding technologies and argon beam electro-coagulation. In the United States, fibrin, acrylate and argon beam electro-coagulation have received the most attention. None of these technologies adequately control the complex, vigorous bleeding associated with severe internal injuries.
Fibrin tissue adhesives have attracted considerable attention due to the high bio-compatibility associated with fibrin monomers. Fibrin tissue adhesives are administered as two components and work by forming an artificial fibrin clot over the effected area. The fibrinogen and Factor XIII component is delivered to the wound site followed by a thrombin and calcium ion solution which initiates the conversion of fibrinogen into fibrin monomers. Fibrin tissue adhesives exhibit relatively weak tissue binding properties, have a fairly long set-up time and are not suitable for use in treating large, aggressively bleeding surfaces. The amount of fibrin required to produce a satisfactory adhesive requires multiple blood donors which increases the risk of transmitting blood borne diseases. These risks will be significantly reduced as recombinant coagulation factors and fibrin become more readily available.
Fibrin based tissue adhesives have been described in a number of U.S. patents, the most relevant of those include U.S. Pat. Nos. 4,414,976, 4,909,251, 5,219,328, 5,395,923, 5,407,671, 5,464,471, 5,804,428 and 5,814,022. U.S. Pat. No. 4,414,976 describes the basic fibrin based tissue sealant and discloses the fundamental theory associated with its biological activity. The remaining patents cited above are primarily directed at novel means for delivering fibrin and the required clotting agents to the wound site in a convenient fashion making the use of this tissue adhesive more acceptable to physicians. U.S. Pat. No. 5,407,671 addresses the transmission of blood borne pathogens and is directed at minimizing this inherent risk, while U.S. Pat. No. 5,464,471 is directed to recombinant forms of fibrin and application techniques thereof. However, none of these patents discuss the use of a fibrin based tissue adhesive for controlling vigorous bleeding, tissues.
Gelatin Resorcin Aldehyde Tissue Adhesives (GRATA) are currently available in Germany for use in conjunction with cardiovascular surgery. These compounds are generally used as reinforcement or leathering agents on fragile tissues. Gelatin Resorcin Aldehyde Tissue Adhesives are composed of heated gelatin that is mixed in situ with a cross-linking agent such as glutaraldehyde or formaldehyde. In general, GRATAs are relatively easy to apply and have moderately good adhesive qualities. However, GRATA do not possess adhesive qualities sufficient to seal large areas of vigorously bleeding tissues and there are reports of post surgical inflammation in rabbits indicating problems with bio-compatibility. U.S. Pat. No. 5,292,333 describes a more recent GRATA development but does not suggest that the claimed tissue adhesive would be suitable for sealing large surface areas of vigorously bleeding tissues. The examples described therein are limited to vascular grafts.
U.S. Pat. No. 5,583,114 discloses an albumin based tissue adhesive prepared using an alkaline solution of human serum albumin that is cross-linked with polyethylene glycol. The resulting tissue adhesive is intended for use as an adjunct or replacement of sutures, stables, tapes and/or bandages. Other proposed uses include post-surgical applications to reduce tissue adhesions, sealing tissues to prevent or control blood or other fluid leaks at suture or staple sites and for controlling leaks in the pulmonary system. Treating large surface areas of vigorously bleeding tissues is not described.
Acrylates are semi-crystalline compounds that tend to fracture under stress which can result in wound healing inhibition. The cyanoacrylates have been exhaustively studied and is the most successful acrylate class used as tissue adhesives. N-isobutyl and N-butylcyanoacrylate were initially selected for development after animal tests suggested that these compounds demonstrated superior tissue adhesiveness and minimal tissue inflammation. N-butylcyanoacrylate is available outside the U.S. for human applications and as an approved veterinary compound within the U.S.
Acrylate tissue adhesives require a dry field for application, fragment easily, are non-bio-absorbable and the polymerization can be extremely exothermic. It has also been reported that the ridged acrylate polymer is nonporous and prevents cell communication and movement which significantly retards would healing. This combination of adverse physical qualities has significantly limited the use of acrylate tissue adhesives with internal applications. Several U.S. patents have been granted in this area of tissue adhesive research including U.S. Pat. Nos. 3,483,870, 3,995,641, and 5,350,798. The compounds described in these patents are primarily intended for sealing superficial cuts and wounds and not intended to control the vigorous bleeding associated with massive injuries to vital organs.
Tissue welding is an area where significant research and development has been focused. Numerous U.S. patents have been issued in this area including four assigned to Fusion Medical Technologies, Inc. of Mountain View, Calif. U.S. Pat. No. 5,669,934 describes the use of a preformed sheet made of collagen, gelatin and mixtures thereof combined with a plastisizer which is sealed to the injured tissue using radio frequencies between 20 and 120 watts. The principle application for this device is the repair of severed and torn tissues including blood vessels, ducts, muscle, fascia, tendon and bone. Although bleeding is often a collateral consequence of injuries to these tissues, control of vigorous bleeding over large surface areas is not disclosed in the '934 patent.
Fusion Technologies U.S. Pat. Nos. 5,690,675, 5,749,895 and 5,824,015 also use patches made from collagen and/or gelatin which are used in conjunction with a device which emits sufficient radio frequency or optical energy to literally weld the patch into place. These devises are particularly well suited for repairing severed tissues, veins, nerves, tendons and muscle where strong, rapid structural repair is required. However, this process does not lend itself to sealing large vigorously bleeding surfaces and such use is not described in the above cited patents.
A hybrid technology has been developed and is disclosed in U.S. Pat. Nos. 5,209,776 and 5,292,362 (Bass patents). These patents describe the development of a tissue adhesive that is principally intended to be used in conjunction with a laser to weld severed tissues and/or prosthetic material together or to form a water tight seal for tissues or prosthetic devices. However, in some cases the tissue adhesive described will spontaneously weld tissues together without the use of an external energy source. The Bass patents disclose an adhesive comprising a first component of fibrous and/or globular proteins, preferably collagen and albumin, which can be used either together or separately and combined with a second component that is made of proteoglycans, glycoproteins, saccharides, polyalcohols, proteins, gels, or similar compounds. The second component provides a matrix, or foundation, for the first component to complex with and form a gel or solution. The resulting gel or solution can be subsequently modified with viscosity agents, bonding enhances and polar dyes which alter the tissue bonding effects when used in conjunction with a laser.
In the Bass patents neither the collagen nor the albumin are ultrasonically modified and the use of both proteins is not required. In the present invention the albumin and collagen are ultrasonically treated and are used together in a synergistic fashion. Furthermore, there is no chemical cross-linking of the proteins used in the Bass patents. Equally important is that neither Bass patent discloses the use of the adhesive system described for controlling large surface areas of complex, vigorously bleeding tissues.
Argon beam high electro-coagulation is a physical technique, not a tissue adhesive per se. High frequency energy is applied directly to the tissue surface causing the rapid evaporation of water resulting in coagulation. However, this process has not proven successful in treating large tissue surface areas and is especially ineffective in patients with coagulopathies.
A number of interesting approached to wound and tissue sealing are described in U.S. Pat. Nos. 4,804,691, 5,445,597, 5,571,080, 5,788,662, and 5,830,700. These include recombinant hybrid proteins, fibrin/thrombin dispensing devises, adhesive pads, and novel polyester compounds. However, none of these devices adequately address the need for a tissue adhesive suitable for emergency use involving traumatic injuries resulting in large surfaces of complex, vigorously bleeding tissues.
The preceding review of the prior art demonstrates the dearth of technical advances in controlling severe bleeding situations using bio-compatible adhesives. In the four centuries since crude sealants consisting of rosewater, turpentine and eggs were first introduced the only significant advance has been Trueta's development of plasterized cotton over 100 years ago. The present invention offers the first acceptable alternative to crude packing techniques currently practiced in trauma centers throughout the world and represents a novel, technically significant and life savings advance in the medial sciences.
It is therefore the object of the present invention to produce a tissues adhesive that is bio-compatible, bio-absorbable, does not interfere with tissue healing, has sufficient adhesive strength to control vigorous bleeding over large surface areas, can be applied rapidly to a variety of tissues and is suitable for use in patients with coagulation disorders.